Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous CYBB regulation and expression.

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene, resulting in the inability of phagocytic cells to eliminate infections. To design a lentiviral vector (LV) capable of recapitulating the endogenous regulation and expression of CYBB, a bioinformatics-guided approach was used to elucidate the cognate enhancer elements regulating the native CYBB gene. Using this approach, we analyzed a 600-kilobase topologically associated domain of the CYBB gene and identified endogenous enhancer elements to supplement the CYBB promoter to develop MyeloVec, a physiologically regulated LV for the treatment of X-CGD. When compared with an LV currently in clinical trials for X-CGD, MyeloVec showed improved expression, superior gene transfer to hematopoietic stem and progenitor cells (HSPCs), corrected an X-CGD mouse model leading to complete protection against Burkholderia cepacia infection, and restored healthy donor levels of antimicrobial oxidase activity in neutrophils derived from HSPCs from patients with X-CGD. Our findings validate the bioinformatics-guided design approach and have yielded a novel LV with clinical promise for the treatment of X-CGD.

Impact of Sleep Disorders and Disturbed Sleep on Brain Health: A Scientific Statement From the American Heart Association.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Outcomes in the Year After First-Ever Ischemic Stroke in a Bi-Ethnic Population.

OBJECTIVE: To investigate stroke outcomes at 3, 6, and 12 months post-stroke overall and by ethnicity in a population-based, longitudinal study. METHODS: First-ever ischemic strokes (2014-2019, n = 1,332) among Mexican American persons (n = 807) and non-Hispanic white persons (n = 525) were identified from the Brain Attack Surveillance in Corpus Christi Project. Data were collected from patient or proxy interviews (baseline, 3, 6, and 12 months post-stroke) and medical records, including functional (activities of daily living/instrumental activities of daily living score), neurological (National Institutes of Health Stroke Scale), cognitive (Modified Mini-Mental State Examination), and quality of life (QOL) outcomes (12-domain Stroke-specific Quality of Life scale). Outcome trajectories were analyzed using multivariable adjusted linear models, with generalized estimating equations to account for within-subject correlations; interactions between ethnicity and time were included to investigate ethnic differences in outcomes. RESULTS: The median age was 67 years (interquartile range 58,78), 48.5% were women, and 60.6% were Mexican American persons. For all outcomes, significant improvement was seen between 3 and 6 months (p < 0.05 for all), with stability between 6 and 12 months. Mexican American persons had significantly worse outcomes compared with non-Hispanic white persons at all time points (3, 6, and 12 months), with the exception of the National Institutes of Health Stroke Scale, which did not differ by ethnicity at 6 and 12 months, and the average change in outcomes did not vary significantly by ethnicity. INTERPRETATION: Outcomes were at their worst at 3 months post-stroke, and ethnic disparities were already present, suggesting the need for early assessment and strategies to improve outcomes and possibly reduce disparities. ANN NEUROL 2023;93:348-356.

Association between sleep-disordered breathing and post-stroke fatigue in patients with ischemic stroke.

OBJECTIVES: Post-stroke fatigue (PSF) is common and often disabling. Sleep-disordered breathing (SDB) is highly prevalent among stroke survivors and can cause fatigue. We explored the relationship between SDB and PSF over time. MATERIALS AND METHODS: Ischemic stroke (IS) patients within the BASIC project were offered SDB screening with a well-validated cardiopulmonary sleep apnea test at 0, 3-, 6-, and 12-months post-stroke. The primary exposure was the respiratory event index (REI; sum of apneas plus hypopneas per hour). The primary outcome was PSF, measured by the SF-36 vitality scale. Associations between REI and PSF were evaluated using linear regression including time-by-REI interactions, allowing the effect of REI to vary over time. RESULTS: Of the 411 IS patients who completed at least one outcome interview, 44 % were female, 61 % Mexican American (MA), 26 % non-Hispanic white, with a mean age of 64 (SD 10). Averaged across timepoints, REI was not associated with PSF. In a time-varying model, higher REI was associated with greater PSF at 3-months (ß = 1.75, CI = 0.08, 3.43), but not at 6- or 12-months. Across timepoints, female sex, depressive symptoms, and comorbidity burden were associated with greater PSF, whereas MA ethnicity was associated with less PSF. CONCLUSIONS: Higher REI was associated with modestly greater PSF in the early post-stroke period, but no association was observed at 6 months and beyond. SDB may be a modest modifiable risk factor for early PSF, but its treatment is unlikely to have a substantial impact on long-term PSF. MA ethnicity seems to be protective against PSF.

Association of Neighborhood Recreation Centers and Poststroke Outcomes in a Population-Based Cohort.

BACKGROUND: Higher neighborhood socioeconomic status has been favorably associated with stroke outcomes. This may be due to these areas having more beneficial resources such as recreational centers. We aimed to determine if neighborhood density of recreation centers is favorably associated with stroke outcomes. METHODS: We conducted analyses of data from the Brain Attack Surveillance in Corpus Christi project, a cohort of stroke survivors ≥45 years of age residing in Nueces County, TX (2009-2020). We included non-Hispanic White and Mexican American incident stroke survivors, who were not institutionalized prestroke and completed baseline and follow-up assessments (N=1392). We calculated the density of fitness and recreational sports centers within their residential census tract during the year of their stroke. Outcomes included function (self-ratings on activities of daily living and instrumental activities of daily living), cognition (modified mini-mental state exam), depression (Patient Health Questionnaire-8), and quality of life (abbreviated Stroke-Specific Quality of Life Scale). We fit confounder-adjusted gamma-distributed mixed generalized linear models with a log link for each outcome and considered interaction with stroke severity. RESULTS: On average, participants were 65 years old, 53% male, and 63% Mexican American. Median recreational centers were 1.60 per square mile (interquartile range, 0.41-3.06). Among moderate-severe stroke survivors, greater density of recreation centers (75th versus 25th percentile) was associated with more favorable function and possibly quality of life (activities of daily living/instrumental activities of daily living, 4.8% change [95% CI, -0.11% to -9.27%]; Stroke-Specific Quality of Life Scale, 3.7% change [95% CI, -0.7% to 8.2%]). Minimal nonsignificant differences were observed among the overall stroke population and those with mild stroke. CONCLUSIONS: The availability of recreation centers may be beneficial for poststroke function and quality of life among those with moderate-severe stroke. If further research confirms recreation centers to be beneficial, this could inform rehabilitation following stroke.

Longitudinal Assessment of Sleep Apnea in the Year After Stroke in a Population-Based Study.

BACKGROUND: The aim of this study was to characterize change in sleep-disordered breathing severity in the year following stroke, overall, and by ethnicity, within the population-based Brain Attack Surveillance in Corpus Christi Project. METHODS: First-ever ischemic strokes (n=414) were ascertained by active and passive surveillance and validated by stroke-trained physicians. Patients with stroke were invited to participate in portable sleep apnea testing (ApneaLink Plus) at baseline and 3, 6, and 12 months poststroke. Sleep-disordered breathing severity was assessed by the respiratory event index (apneas and hypopneas/hour of recording). The component obstructive apnea index and central apnea index were also assessed. Time and ethnicity effects on outcomes, as well as ethnic differences in time effects, were analyzed using generalized estimating equations with multivariable adjustment for confounding factors. RESULTS: Mean age (n=414) was 63.9 years (SD=10.9); 68.4% were Mexican American. Baseline mean respiratory event index, obstructive apnea index, and central apnea index were 21.3 (SD=16.6), 8.6 (SD=11.5), and 1.5 (SD=3.2), respectively. There was no time effect on respiratory event index (P=0.35) but obstructive apnea index increased over time (P<0.01). Averaged over follow-up, respiratory event index and obstructive apnea index were significantly higher in Mexican American than non-Hispanic White persons. No ethnic difference in the time effect was found for either outcome. For central apnea index, there was an ethnicity-time interaction (P=0.01) such that central apnea index increased in non-Hispanic White but did not change in Mexican American persons. CONCLUSIONS: Sleep-disordered breathing severity was significant and stable for most individuals in the year after stroke. These results do not confirm previous reports of diminishing sleep-disordered breathing severity over time after stroke and would support early assessment and treatment where indicated.

Operando Investigation of Locally Enhanced Electric Field Treatment (LEEFT) Harnessing Lightning-Rod Effect for Rapid Bacteria Inactivation.

The growth of undesired bacteria causes numerous problems. Here, we show that locally enhanced electric field treatment (LEEFT) can cause rapid bacteria inactivation by electroporation. The bacteria inactivation is studied in situ at the single-cell level on a lab-on-a-chip that has nanowedge-decorated electrodes. Rapid bacteria inactivation occurs at the nanowedge tips where the electric field is enhanced due to the lightning-rod effect. Electroporation induced by the locally enhanced electric field is the predominant mechanism. The antimicrobial performance depends on the strength of the enhanced electric field instead of the applied voltage, and no generation of reactive oxygen species (ROS) is detected when >90% bacteria inactivation is achieved. Quick membrane pore closure under lower voltages confirms that electroporation is induced in LEEFT. This work is the first-time visualization and mechanism elucidation of LEEFT for bacteria inactivation at the single-cell level, and the findings will provide strong support for its future applications.

Obstructive Sleep Apnea and Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Obstructive sleep apnea (OSA) is characterized by recurrent complete and partial upper airway obstructive events, resulting in intermittent hypoxemia, autonomic fluctuation, and sleep fragmentation. Approximately 34% and 17% of middle-aged men and women, respectively, meet the diagnostic criteria for OSA. Sleep disturbances are common and underdiagnosed among middle-aged and older adults, and the prevalence varies by race/ethnicity, sex, and obesity status. OSA prevalence is as high as 40% to 80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke. Despite its high prevalence in patients with heart disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. We recommend screening for OSA in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with tachy-brady syndrome or ventricular tachycardia or survivors of sudden cardiac death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea. All patients with OSA should be considered for treatment, including behavioral modifications and weight loss as indicated. Continuous positive airway pressure should be offered to patients with severe OSA, whereas oral appliances can be considered for those with mild to moderate OSA or for continuous positive airway pressure-intolerant patients. Follow-up sleep testing should be performed to assess the effectiveness of treatment.

Racial and ethnic differences in sleep-disordered breathing and sleep duration among stroke patients.

OBJECTIVE: We sought to characterize racial and ethnic differences in pre- and post-stroke sleep-disordered breathing (SDB) and pre-stroke sleep duration. METHODS: Within the Brain Attack Surveillance in Corpus Christi cohort of patients with ischemic stroke (8/26/2010-1/31/2020), pre-stroke SDB risk was assessed retrospectively using the Berlin Questionnaire. Post-stroke SDB was defined by prospective collection of the respiratory event index (REI) using the ApneaLink Plus performed shortly after stroke. Pre-stroke sleep duration was self-reported. We used separate regression models to evaluate the association between race/ethnicity and each outcome (pre-stroke SDB, post-stroke SDB, and pre-stroke sleep duration), without and with adjustment for potential confounders. RESULTS: There was no difference in pre-stroke risk of SDB between Black and non-Hispanic white (NHW) participants (odds ratio (OR) 1.07, 95% CI 0.77-1.49), whereas MA (Mexican American), compared to NHW, participants had a higher risk of SDB before adjusting for demographic and clinical variables (OR 1.26, 95% CI 1.08-1.47). Post-stroke SDB risk was higher in MA (estimate 1.16, 95% CI 1.06-1.28) but lower in Black (estimate 0.79, 95% CI 0.65-0.96) compared to NHW participants; although, only the ethnic difference remained after adjustment. MA and Black participants had shorter sleep duration than NHW participants (OR 0.83, 95% CI 0.72-0.96 for MA; OR 0.67, 95% CI 0.49-0.91 for Black participants) before but not after adjustment. CONCLUSIONS: Racial/ethnic differences appear likely to exist in pre- and post-stroke SDB and pre-stroke sleep duration. Such differences might contribute to racial/ethnic disparities in stroke incidence and outcomes.

Trials in Sleep Apnea and Stroke: Learning From the Past to Direct Future Approaches.

Few randomized controlled trials have evaluated the effectiveness of continuous positive airway pressure (CPAP) in reducing recurrent vascular events and mortality in poststroke obstructive sleep apnea (OSA). To date, results have been mixed, most studies were underpowered and definitive conclusions are not available. Using lessons learned from prior negative trials in stroke, we reappraise prior randomized controlled trials that examined the use of CPAP in treating poststroke OSA and propose the following considerations: (1) Intervention-based changes, such as ensuring that patients are using CPAP for at least 4 hours per night (eg, through use of improvements in CPAP technology that make it easier for patients to use), as well as considering alternative treatment strategies for poststroke OSA; (2) Population-based changes (ie, including stroke patients with severe and symptomatic OSA and CPAP noncompliers); and (3) Changes to timing of intervention and follow-up (ie, early initiation of CPAP therapy within the first 48 hours of stroke and long-term follow-up calculated in accordance with sample size to ensure adequate power). Given the burden of vascular morbidity and mortality in stroke patients with OSA, there is a strong need to learn from past negative trials and explore innovative stroke prevention strategies to improve stroke-free survival.

Overnight Rostral Fluid Shifts Exacerbate Obstructive Sleep Apnea After Stroke.

Background and Purpose: Overnight shifts of fluid from lower to upper compartments exacerbate obstructive sleep apnea (OSA) in some OSA populations. Given the high prevalence of OSA after stroke, decreased mobility and use of IV fluids among hospitalized patients with stroke, and improvement in OSA in the months after stroke, we hypothesized that overnight fluid shifts occur and are associated with OSA among patients with subacute ischemic stroke. Methods: Within a population-based project, we performed overnight sleep apnea tests (ApneaLink Plus) during ischemic stroke hospitalizations. Before sleep that evening, and the following morning before rising from bed, we assessed neck and calf circumference, and leg fluid volume (bioimpedance spectroscopy). The average per subject overnight change in the 3 fluid shift measurements was calculated and compared with zero. Linear regression was used to test the crude association between each of the 3 fluid shift measurements and the respiratory event index (REI). Results: Among the 292 participants, mean REI was 24 (SD=18). Within individuals, calf circumference decreased on average by 0.66 cm (SD=0.75 cm, P<0.001), leg fluid volume decreased by a mean of 135.6 mL (SD=132.8 mL, P<0.001), and neck circumference increased by 0.20 cm (SD=1.71 cm, P=0.07). In men, when the overnight change of calf circumference was negative, an interquartile range (0.8 cm) decrease in calf circumference overnight was significantly associated with a 25.1% increase in REI (P=0.02); the association was not significant in women. The relationship between overnight change in leg fluid volume and REI was U shaped. Conclusions: This population-based, multicenter, cross-sectional study showed that in hospitalized patients with ischemic stroke, nocturnal rostral fluid shifts occurred, and 2 of the 3 measures were associated with greater OSA severity. Interventions that limit overnight fluid shifts should be tested as potential treatments for OSA among patients with subacute ischemic stroke.

Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

BACKGROUND: Dual antiplatelet therapy (DAPT) after ischemic stroke or transient ischemic attack may reduce recurrent stroke but also increase severe bleeding compared with single antiplatelet therapy (SAPT). The American Heart Association/American Stroke Association convened an evidence review committee to perform a systematic review and meta-analysis of the benefits and risks of DAPT compared with SAPT for secondary ischemic stroke prevention. METHODS: The Medline, Embase, and Cochrane databases were searched on December 5, 2019, to identify phase III or IV randomized controlled trials (n≥100) from December 1999 to December 2019. We calculated unadjusted relative risks (RRs) and performed meta-analyses of studies based on the duration of treatment (short [≤90 days] versus long [>90 days]). RESULTS: Three short-duration randomized controlled trials were identified that enrolled mostly patients with minor stroke or high risk transient ischemic attack. In these trials, DAPT, compared with SAPT, was associated with a lower 90-day risk of recurrent ischemic stroke (pooled RR, 0.68 [95% CI, 0.55-0.83], I 2=37.1%). There was no significant increase in major bleeding with DAPT in short-duration trials (pooled RR, 1.88 [95% CI, 0.93-3.83], I 2=8.9%). In 2 long-duration treatment randomized controlled trials (mean treatment duration, 18-40 months), DAPT was not associated with a significant reduction in recurrent ischemic stroke (pooled RR, 0.89 [95% CI, 0.79-1.02], I 2=1.4%), but was associated with a higher risk of major bleeding (pooled RR, 2.42 [95% CI, 1.37-4.30], I 2=75.5%). CONCLUSIONS: DAPT was more effective than SAPT for prevention of secondary ischemic stroke when initiated early after the onset of minor stroke/high-risk transient ischemic attack and treatment duration was <90 days. However, when the treatment duration was longer and initiated later after stroke or transient ischemic attack onset, DAPT was not more effective than SAPT for ischemic stroke prevention and it increased the risk of bleeding.

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small ß-Globin Locus Control Region Elements.

ß-globin lentiviral vectors (ß-LV) have faced challenges in clinical translation for gene therapy of sickle cell disease (SCD) due to low titer and sub-optimal gene transfer to hematopoietic stem and progenitor cells (HSPCs). To overcome the challenge of preserving efficacious expression while increasing vector performance, we used published genomic and epigenomic data available through ENCODE to redefine enhancer element boundaries of the ß-globin locus control region (LCR) to construct novel ENCODE core sequences. These novel LCR elements were used to design a ß-LV of reduced proviral length, termed CoreGA-AS3-FB, produced at higher titers and possessing superior gene transfer to HSPCs when compared to the full-length parental ß-LV at equal MOI. At low vector copy number, vectors containing the ENCODE core sequences were capable of reversing the sickle phenotype in a mouse model of SCD. These studies provide a ß-LV that will be beneficial for gene therapy of SCD by significantly reducing the cost of vector production and extending the vector supply.

Tissue-Based Stroke Definition Impacts Stroke Incidence but not Ethnic Differences.

OBJECTIVES: We explored how the new, tissue-based stroke definition impacted incidence estimates, including an ethnic comparison, in a population-based study. METHODS: Stroke patients, May, 2014-May, 2016 in Nueces County, Texas were ascertained and validated using source documentation. Overall, ethnic-specific and age-specific Poisson regression models were used to compare first-ever ischemic stroke and intracerebral hemorrhage (ICH) incidence between old and new stroke definitions, adjusting for age, ethnicity, sex, and National Institutes of Health Stroke Scale score. RESULTS: Among 1308 subjects, 1245 (95%) were defined as stroke by the old definition and 63 additional cases (5%) according to the new. There were 12 cases of parenchymal hematoma (PH1 or PH2) that were reclassified from ischemic stroke to ICH. Overall, incidence of ischemic stroke was slightly higher under the new compared to the old definition (RR 1.07; 95% CI 0.99-1.16); similarly higher in both Mexican Americans (RR 1.06; 95% CI 1.00-1.12) and Non Hispanic whites (RR 1.09, 95% CI 0.97-1.22), p(ethnic difference)=0.36. Overall, incidence of ICH was higher under the new definition compared to old definition (RR 1.16; 95% CI 1.05-1.29), similarly higher among both Mexican Americans (RR 1.14; 95% CI 1.06-1.23) and Non Hispanic whites (RR 1.20, 95% CI 1.03-1.39), p(ethnic difference)=0.25. CONCLUSION: Modest increases in ischemic stroke and ICH incidence occurred using the new compared with old stroke definition. There were no differences between Mexican Americans and non Hispanic whites. These estimates provide stroke burden estimates for public health planning.

Process Evaluation of a Faith-Based Multicomponent Behavioral Intervention to Reduce Stroke Risk in Mexican Americans in a Catholic Church Setting: The SHARE (Stroke Health and Risk Education) Project.

Church-based stroke prevention programs for Hispanics are underutilized. The Stroke Health and Risk Education (SHARE) project, a multicomponent cluster-randomized trial, addressed key stroke risk factors among predominantly Mexican Americans in a Catholic Church setting. Process evaluation components (implementation, mechanisms of impact, and context) are described. Partner support promoted positive health behavior change. Motivational interviewing calls were perceived as helpful, however, barriers with telephone delivery were encountered. Intervention exposure was associated with theory constructs for targeted behaviors. We conclude that health behavior interventions to prevent stroke can be successfully implemented for Mexican Americans within a Catholic Church setting, with parish priest support.

Trends in Stroke Recurrence in Mexican Americans and Non-Hispanic Whites.

BACKGROUND AND PURPOSE: Stroke incidence and mortality are declining rapidly in developed countries. Little data on ethnic-specific stroke recurrence trends exist. Fourteen-year stroke recurrence trend estimates were evaluated in Mexican Americans and non-Hispanic whites in a population-based study. METHODS: Recurrent stroke was ascertained prospectively in the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in Texas, between 2000 and 2013. Incident cases were followed forward to determine 1- and 2-year recurrence. Fine & Gray subdistribution hazard models were used to estimate adjusted trends in the absolute recurrence risk and ethnic differences in the secular trends. The ethnic difference in the secular trend was examined using an interaction term between index year and ethnicity in the models adjusted for age, sex, hypertension, diabetes mellitus, smoking, atrial fibrillation, insurance, and cholesterol and relevant interaction terms. RESULTS: From January 1, 2000 to December 31, 2013 (N=3571), the cumulative incidence of 1-year recurrence in Mexican Americans decreased from 9.26% (95% CI, 6.9%-12.43%) in 2000 to 3.42% (95% CI, 2.25%-5.21%) in 2013. Among non-Hispanic whites, the cumulative incidence of 1-year recurrence in non-Hispanic whites decreased from 5.67% (95% CI, 3.74%-8.62%) in 2000 to 3.59% (95% CI, 2.27%-5.68%) in 2013. The significant ethnic disparity in stroke recurrence existed in 2000 (risk difference, 3.59% [95% CI, 0.94%-6.22%]) but was no longer seen by 2013 (risk difference, -0.17% [95% CI, -1.96% to 1.5%]). The competing 1-year mortality risk was stable over time among Mexican Americans, while for non-Hispanic whites it was decreasing over time (difference between 2000 and 2013: -4.67% [95% CI, -8.72% to -0.75%]). CONCLUSIONS: Mexican Americans had significant reductions in stroke recurrence despite a stable death rate, a promising indicator. The ethnic disparity in stroke recurrence present early in the study was gone by 2013.

Sleep apnea and stroke.

PURPOSE OF REVIEW: Stroke and sleep apnea are highly prevalent conditions with a physiologically plausible bidirectional relationship. This review addresses prestroke sleep apnea, wake-up stroke and sleep apnea, and poststroke sleep apnea, with an attempt to highlight research published in the last 18 months. RECENT FINDINGS: Sleep apnea is highly prevalent poststroke. Poststroke sleep apnea is associated with worse poststroke functional and cognitive outcomes and a higher risk of recurrent stroke. Physiologic tests are needed to diagnose sleep apnea in poststroke patients as sleep apnea questionnaires do not perform well in this population. The role of CPAP in poststroke management is not yet well established. SUMMARY: Sleep apnea is a well established independent risk factor for stroke that confers an approximately two-fold increased risk of incident stroke. Sleep apnea is highly prevalent poststroke and is associated with worse outcomes after stroke. Sleep apnea is an attractive target for research addressing secondary stroke prevention and recovery.

Sleep-disordered breathing and poststroke outcomes.

OBJECTIVE: To examine the association between sleep-disordered breathing and stroke outcomes, and determine the contribution of sleep-disordered breathing to outcome disparities in Mexican Americans. METHODS: Ischemic stroke patients (n = 995), identified from the population-based Brain Attack Surveillance in Corpus Christi Project (2010-2015), were offered participation in a sleep-disordered breathing study including a home sleep apnea test (ApneaLink Plus). Sleep-disordered breathing (respiratory event index ≥10) was determined soon after stroke. Neurologic, functional, cognitive, and quality of life outcomes were assessed at 90 days poststroke. Regression models were used to assess associations between sleep-disordered breathing and outcomes, adjusted for sociodemographics, prestroke function and cognition, health-risk behaviors, stroke severity, and vascular risk factors. RESULTS: Median age was 67 years (interquartile range [IQR] = 59-78); 62.1% were Mexican American. Median respiratory event index was 14 (IQR = 6-25); 62.8% had sleep-disordered breathing. Sleep-disordered breathing was associated with worse functional outcome (mean difference in activities of daily living/instrumental activities of daily living score = 0.15, 95% confidence interval [CI] = 0.01-0.28) and cognitive outcome (mean difference in modified Mini-Mental State Examination = -2.66, 95% CI = -4.85 to -0.47) but not neurologic or quality of life outcomes. Sleep-disordered breathing accounted for 9 to 10% of ethnic differences in functional and cognitive outcome and was associated with cognitive outcome more strongly for Mexican Americans (ß = -3.97, 95% CI = -6.63 to -1.31) than non-Hispanic whites (ß = -0.40, 95% CI = -4.18 to 3.39, p-interaction = 0.15). INTERPRETATION: Sleep-disordered breathing is associated with worse functional and cognitive function at 90 days poststroke. These outcomes are reasonable endpoints for future trials of sleep-disordered breathing treatment in stroke. If effective, sleep-disordered breathing treatment may somewhat lessen ethnic stroke outcome disparities. ANN NEUROL 2019;86:241-250.

Improving Gene Editing Outcomes in Human Hematopoietic Stem and Progenitor Cells by Temporal Control of DNA Repair.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated system (Cas9)-mediated gene editing of human hematopoietic stem cells (hHSCs) is a promising strategy for the treatment of genetic blood diseases through site-specific correction of identified causal mutations. However, clinical translation is hindered by low ratio of precise gene modification using the corrective donor template (homology-directed repair, HDR) to gene disruption (nonhomologous end joining, NHEJ) in hHSCs. By using a modified version of Cas9 with reduced nuclease activity in G1 phase of cell cycle when HDR cannot occur, and transiently increasing the proportion of cells in HDR-preferred phases (S/G2), we achieved a four-fold improvement in HDR/NHEJ ratio over the control condition in vitro, and a significant improvement after xenotransplantation of edited hHSCs into immunodeficient mice. This strategy for improving gene editing outcomes in hHSCs has important implications for the field of gene therapy, and can be applied to diseases where increased HDR/NHEJ ratio is critical for therapeutic success. Stem Cells 2019;37:284-294.